US7994343B2 - Process for the production of atorvastatin calcium in amorphous form - Google Patents

Process for the production of atorvastatin calcium in amorphous form Download PDF

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US7994343B2
US7994343B2 US10/549,890 US54989004A US7994343B2 US 7994343 B2 US7994343 B2 US 7994343B2 US 54989004 A US54989004 A US 54989004A US 7994343 B2 US7994343 B2 US 7994343B2
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atorvastatin calcium
calcium
solvent
water
solution
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US20100197941A1 (en
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Yatendra Kumar
Saridi Madhava Dileep Kumar
Swargam Sathyanarayana
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Ranbaxy Laboratories Ltd
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Ranbaxy Laboratories Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics

Definitions

  • Atorvastatin is known by the chemical name [R—(R*,R*)]-2-(4-fluorophenyl)- ⁇ , ⁇ -dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid.
  • the hemi-calcium salt of atorvastatin is useful as an inhibitor of the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase) and is thus useful as a hypolipidemic and hypocholesterolemic agent.
  • Several processes have been reported for the preparation of amorphous form of atorvastatin calcium in U.S. Pat. Nos. 6,528,660 and 6,613,916; U.S. Patent Application Publication Nos. 2002/183378 and 2003/109569; and International (PCT) Patent Applications WO 01/2899, WO 02/57228, WO 02/83637, WO 02/83638, WO 03/18547 and WO 03/68739.
  • a process for the production of atorvastatin calcium in amorphous form comprising:
  • a process for purifying atorvastatin calcium comprising dissolving crude atorvastatin calcium in a mixture of tetrahydrofuran and methanol, and precipitating with water to obtain pure atorvastatin calcium in crystalline form.
  • a process for the production of stabilized atorvastatin calcium in amorphous form comprising:
  • a process for the production of atorvastatin calcium in amorphous form comprising:
  • the acid used for deketalization of Compound H to afford Compound I may be an inorganic acid.
  • inorganic acids include hydrochloric, hydrobromic, sulphuric, phosphoric and nitric acids.
  • Suitable water-miscible solvents for the deketalization process include acetonitrile; alcohols such as methanol, ethanol, propanol, and isopropanol; cyclic ethers such as dioxane and tetrahydrofuran; ketones such as acetone and mixtures thereof.
  • Compound I can be hydrolysed with an alkali metal hydroxide such as sodium hydroxide, potassium hydroxide and lithium hydroxide.
  • the reaction mixture may be maintained at a pH of at least 9, for example, about 12, to result in efficient hydrolysis and to minimize side product formation.
  • the reaction mixture is then washed with a water-immiscible or slightly water-miscible solvent to remove unreacted compounds and other impurities.
  • Suitable solvents for the washing include ethers such as methyl tertiary butyl ether, diethyl ether, methyl ethyl ether and dibutyl ether; esters such as ethyl acetate and isopropyl acetate; and hydrocarbons such as toluene and petroleum ether.
  • the solution of alkali metal salt of atorvastatin obtained is reacted with calcium hydroxide or a calcium salt such as calcium acetate, calcium chloride, calcium sulfate, calcium nitrate and calcium phosphate.
  • the reaction may be performed at a temperature of about 45 to 55° C.
  • the pH of the solution of alkali metal salt of atorvastatin may be lowered to about 7.8 to 8.2 with an acid before addition of the calcium salt to facilitate isolation of crude atorvastatin calcium.
  • Any residual water-immiscible or slightly water-miscible solvent remaining in the reaction mixture may be removed under reduced pressure to aid precipitation.
  • Water may be used as an antisolvent to effect precipitation of crude atorvastatin calcium in good yields. Water may be added at a temperature of about 55 to 65° C. to avoid rapid precipitation and seeds of crystalline atorvastatin calcium may also be added to the mixture.
  • Crude atorvastatin calcium may be isolated in high yields by cooling the reaction mixture to a temperature of about 20 to 35° C. and stirring at the same temperature for several hours before filtration or centrifugation.
  • Crude atorvastatin calcium is purified by crystallization using tetrahydrofuran and methanol as solvents and water as anti-solvent. Purification involves removal of unreacted compounds, side product and other impurities. Tetrahydrofuran, methanol and water may be used in the volume ratio 1:1:4 to obtain atorvastatin calcium of high purity. Water may be added at a temperature of about 60 to 65° C. Seeds of crystalline atorvastatin calcium may be added to facilitate precipitation. In a particular embodiment, seeds of crystalline atorvastatin calcium are added at a temperature of about 50° C. Crystalline atorvastatin calcium may be isolated by cooling the mixture to a temperature of about 30 to 35° C. and stirring at the same temperature for several hours before filtration or centrifugation.
  • Crystalline pure atorvastatin calcium may be converted into the amorphous form by methods known in the art such as U.S. Pat. Nos. 6,528,660 and 6,613,916; International (PCT) Patent Applications WO 01/28999, WO 03/99785, WO 03/78379, WO 03/18547 and WO 02/57228; and U.S. Patent Application Publication No. 2002/183378, which are incorporated herein by reference.
  • Amorphous atorvastatin calcium may also be obtained by having an additional step wherein the pure crystalline atorvastatin calcium (where “pure” is meant in the sense of chemical purity) obtained after step f) is suspended in a mixture of methanol and water in the volume ratio 1 to 5 and stirred with seed crystals of crystalline Form I, to obtain atorvastatin calcium in crystalline Form I.
  • the stirring may be performed at a temperature of about 10 to 65° C., for example, about 30 to 45° C.
  • pure crystalline atorvastatin calcium (where “pure” is meant in the sense of chemical purity) obtained after step f) is suspended in a mixture of methanol and water in the volume ratio 3 to 2 and stirred with seed crystals of crystalline Form II, to obtain atorvastatin calcium in crystalline Form II.
  • the volume of methanol and water mixture may be about 15 to 25 times, for example, about 20 times, the weight of the atorvastatin calcium to be suspended.
  • the stirring may be performed at a temperature of about 10 to 65° C., for example, about 25 to 45° C.
  • a further additional step may be performed wherein crystalline Form I of atorvastatin calcium obtained above is suspended in a mixture of methanol and water in the volume ratio 3 to 2 and stirred with seed crystals of crystalline Form II, to obtain atorvastatin calcium in crystalline Form II.
  • the volume of methanol and water mixture may be about 15 to 25 times, for example, about 20 times, the weight of the atorvastatin calcium to be suspended.
  • the stirring may be performed at a temperature of about 10 to 65° C., for example, about 25 to 45° C.
  • Amorphous atorvastatin calcium may be obtained by dissolving crystalline atorvastatin calcium in a solvent, and adding the resulting solution to an anti-solvent.
  • An anti-solvent is a liquid that does not dissolve atorvastatin calcium.
  • solvents include ketones such as acetone and methyl isobutyl ketone; esters such as ethyl acetate and isopropyl acetate; chlorinated hydrocarbons such as methylene chloride and ethylene dichloride; cyclic ethers such as dioxan and tetrahydrofuran; alcohols such as methanol, ethanol and isopropanol; nitriles such as acetonitrile; dipolar aprotic solvents such as dimethylsulfoxide and dimethylformamide; and mixtures thereof with water.
  • anti-solvents examples include hydrocarbons, such as cyclohexane, hexanes, heptanes, petroleum ethers, toluene, xylene and the like; dialkyl ethers such as diethyl ether, diisopropyl ether, and the like; and can readily be determined by one ordinarily skilled in the art.
  • An antioxidant may be added to the atorvastatin calcium solution to obtain stabilized, amorphous atorvastatin calcium.
  • suitable antoxidants include butylated hydroxyanisole, butylated hydroxytoluene and tertiary-butylated hydroquinone.
  • stabilized atorvastatin calcium means the hemi-calcium salt of atorvastatin having a level of purity, which is provided and maintained through the use of antioxidants.
  • Stabilized, amorphous atorvastatin calcium can be obtained with purity of at least 97%, for example when determined by high performance liquid chromatography (HPLC) analysis.
  • stabilized, amorphous atorvastatin calcium having a purity of at least 99% may be obtained.
  • stabilized, amorphous atorvastatin calcium having a purity of at least 99.5% may be obtained.
  • the atorvastatin calcium solution may be dried (moisture removal) before its addition to the non-solubilizing liquid. This may be accomplished by, for example, filtration through dry molecular sieves. Alternatively or additionally, drying of the solution may be achieved by a process, wherein the solution is made using excess solvent, which is then concentrated to remove moisture from the solution.
  • hydroxylic solvents which may be used for dissolving atorvastatin calcium include alcohols such as methanol, ethanol, propanol, isopropanol, and mixtures thereof with water.
  • non-hydroxylic anti-solvents which may have a higher boiling point than the hydroxylic solvent include hydrocarbons, such as cyclohexane, hexanes, heptanes, petroleum ethers, toluene, xylene and the like; dialkyl ethers such as diisopropyl ether, and the like; and can readily be determined by one ordinarily skilled in the art.
  • the solution of atorvastatin calcium having the desired hydroxylic solvent and non-hydroxylic anti-solvent is concentrated to remove the hydroxylic solvent either partially or completely to precipitate amorphous atorvastatin calcium.
  • an antioxidant may be added to the hydroxylic solution of atorvastatin calcium to obtain stabilized, amorphous atorvastatin calcium.
  • the atorvastatin calcium hydroxylic solution may also be treated as detailed above for moisture removal.
  • Crystalline forms of atorvastatin calcium to be used as seeds may be obtained by methods known in the art such as those described in U.S. 2002/183378, which is incorporated herein by reference, or prepared by processes exemplified herein.
  • the reaction mass was cooled and diluted with toluene.
  • the reaction mixture was then washed initially with aqueous sodium hydroxide solution (0.5 N), then with aqueous hydrochloric acid solution (0.5 N) and followed by brine (10%).
  • the organic layer was treated with activated carbon, and filtered through a hyflo filter.
  • the organic layer was concentrated to 10% of the total volume under vacuum.
  • Isopropyl alcohol (34 L) was then added, and the solvent recovered under vacuum, followed by repeated addition of isopropyl alcohol and solvent recovery under vacuum.
  • the residue was dissolved in isopropyl alcohol and de-ionized water (45 L) was added till turbidity appeared. Further de-ionized water (60 L) was added gradually.
  • the precipitated product was filtered, washed with a mixture of isopropyl alcohol and de-ionized water (2:1) and dried to get the title compound (16.2 Kg, 24.77 moles, 94% by HPLC).
  • the crude product was purified by dissolving in isopropyl alcohol (128 L) at 50 to 55° C., concentrating the solution and cooling the residual mass slowly under stirring.
  • the solid thus obtained was filtered, washed with chilled isopropyl alcohol and dried at 40 to 45° C. to give pure Compound H (13.2 Kg, 20.20 moles, purity: 99% by HPLC).
  • the pH of the reaction mixture obtained above was adjusted to about 12 by adding 10% w/v aqueous sodium hydroxide solution at 25-30° C. and the resulting mixture was stirred for about 6 hours at 25-30° C.
  • the progress of the reaction was monitored by HPLC.
  • the pH of the reaction mixture was monitored and maintained at about 12 throughout the course of the reaction by adding 10% w/v aqueous sodium hydroxide solution. After the reaction was complete, the mass was filtered and concentrated to about 84 L.
  • the crude product obtained above was charged to a reactor containing methanol (16 L) and tetrahydrofuran (40 L). The contents are stirred to get a clear solution and filtered through a sparkler filter followed by washing over hyflo bed with methanol (32 L). The filtrate was heated to 65° C. and refluxed for 30-60 minutes. To this, de-ionised water (about 120 L) was added slowly over a period of 1-2 hours until turbidity appeared. At the onset of turbidity, crystalline atorvastatin calcium Form I seeds (8 g) were added. The contents were stirred for 30 minutes at 68-72° C. and de-ionised water (about 40 L) was added. The contents were cooled to 50° C.
  • atorvastatin calcium Form I seeds 24 g were added with continuous stirring. The contents were further cooled to 35° C. and stirred for 5 hours at 33-35° C. and then filtered. The wet cake was washed with a mixture of tetrahydrofuran, methanol and de-ionized water (volume ratio 1:1:4) and then dried at 50-55° C. under reduced pressure to yield 7.36 Kg of crystalline atorvastatin calcium.
  • the above dried product was added to a reactor containing de-ionized water (108.8 L) and methanol (19.2 L). The contents were stirred for 10 minutes and heated to 45° C. To this, crystalline atorvastatin calcium form I seeds (730 g) were added and the mixture was stirred at 40° C. to 45° C. until the IR spectrum of the sample was comparable with the seed crystals. The contents were filtered and washed with a mixture of de-ionized water and methanol (volume ratio 6:1). The wet cake was dried at 50-55° C. to yield 7.2 Kg of crystalline atorvastatin calcium having a purity of 99.7% determined by HPLC.
  • Tetrahydrofuran (16.38 L) was added to crystalline atorvastatin calcium Form I (6.3 Kg, 5.2 moles) obtained above followed by butylated hydroxyanisole (63 g, 0.5 moles). The contents were stirred for 30 minutes at 20 to 25° C. to get a solution. This solution was filtered over a hyflo bed followed by washing of the hyflo bed with tetrahydrofuran (2.52 L), and the filtrate was collected. The filtrate was added slowly over a period of 4 to 5 hours to cyclohexane (189 L) at 25° C. The contents were stirred for 60 minutes, centrifuged and washed with cyclohexane. The material was dried under vacuum at 60° C. to 70° C. for 12 hours to yield 5.67 Kg of amorphous atorvastatin calcium having a purity of 99.54% determined by HPLC.
  • Tetrahydrofuran (10 L) was added to atorvastatin calcium Form I (1 Kg) obtained as per Example 1 above, followed by butylated hydroxyanisole (3 g). The contents were stirred for 15 minutes at 20 to 25° C. to get a solution. This solution was filtered over hyflo bed followed by washing of the hyflo bed with tetrahydrofuran (0.4 L), and the filtrate was collected and concentrated to a volume of about 3 L at 62 to 70° C. The solution was cooled to 20° C. and added slowly over a period of 4 to 5 hours to cyclohexane (30 L) at 20 to 23° C. The contents were stirred for 60 minutes and filtered.
  • the wet cake was washed with cyclohexane.
  • the material was dried under vacuum at 60° C. to 70° C. for 12 hours to yield 0.9 Kg of amorphous atorvastatin calcium having a purity of 99.45% determined by HPLC.
  • the crude atorvastatin calcium obtained as per Example 1 was charged to a reactor containing methanol (16 L) and tetrahydrofuran (40 L). The contents are stirred to get a clear solution and filtered through a sparkler filter, followed by washing over hyflo bed with methanol (32 L). The filtrate was heated to 65° C. and refluxed for 30-60 minutes. To this, de-ionised water (about 120 L) was added slowly over a period of 1-2 hours until turbidity appeared. The contents were stirred for 30 minutes at 68-72° C. and de-ionised water (about 40 L) was added. The contents were cooled to 35° C. and stirred for 5 hours at 33-35° C. and then filtered.
  • the wet cake was washed with a mixture of tetrahydrofuran, methanol and de-ionized water (volume ratio 1:1:4) and then dried at 50-55° C. under reduced pressure to yield 7.33 Kg of crystalline atorvastatin calcium.
  • Tetrahydrofuran (480 ml) was added to crystalline atorvastatin calcium obtained above in Example 5 (60 g), followed by butylated hydroxyanisole (0.6 g). The contents were stirred, de-ionised water (24 ml) was added and the mixture was stirred for 15 minutes at 20 to 25° C. to get a clear solution.
  • Molecular sieves (240 g, Siliporite NK30 AP® powdered) were added to the solution and the mixture was stirred for 2 hours at 20 to 25° C. This solution was filtered through a molecular sieves bed, followed by washing of the bed with tetrahydrofuran (120 ml).
  • the filtrate was collected and concentrated to a volume of about 210 ml at 60 to 70° C.
  • the concentrated solution was cooled to 25° C. and added slowly over a period of 2 hours to cyclohexane (1800 ml) at 22 to 25° C. under moderate stirring.
  • the contents were stirred vigorously for 30 minutes at the same temperature and filtered.
  • the wet cake was washed with cyclohexane (60 ml).
  • the material was dried under reduced pressure at 60° C. to 70° C. for 6 hours to yield 54 g of amorphous atorvastatin calcium.
  • Siliporite NK30 AP is registered trademark of CECA, France
  • Tetrahydrofuran (10 L) was added to atorvastatin calcium crystalline Form II (1 Kg) followed by butylated hydroxyanisole (3 g). The contents were stirred for 15 minutes at 20 to 25° C. to get a solution. This solution was filtered over a hyflo bed followed by washing of the hyflo bed with tetrahydrofuran (0.4 L), and the filtrate was collected and concentrated to a volume of about 3 L at 62 to 70° C. The solution was cooled to 20° C. and added slowly over a period of 4 to 5 hours to cyclohexane (30 L) at 20 to 23° C. The contents were stirred for 60 minutes and filtered.
  • the wet cake was washed with cyclohexane.
  • the material was dried under vacuum at 60° C. to 70° C. for 12 hours to yield 0.9 Kg of amorphous atorvastatin calcium having a purity of 99.5% determined by HPLC.
  • the obtained suspension was then cooled to 20 to 25° C. with stirring in 30 minutes and filtered.
  • the wet cake was washed with cyclohexane.
  • the material was dried under vacuum at 60° C. to 70° C. for 1 hour to yield 9.0 g of amorphous atorvastatin calcium.
  • n-Butyl lithium and diisopropylamine are mixed at 40° C. for the formation of lithium diisopropylamine.
  • 1,1-Dimethylethyl acetate (Compound B) in tetrahydrofuran is then added at ⁇ 50° C. and the mixture stirred at ⁇ 20 to 25° C. for 1 hour.
  • the reaction mixture is further cooled to ⁇ 50° C. and (R)-ethyl-4-cyano-3-hydroxybutanoate is added maintaining temperature at ⁇ 20 to ⁇ 25° C. and kept at the same temperature for 2 hours.
  • the reaction is monitored for completion by thin layer chromatography.
  • reaction is quenched with a 2 N solution of hydrochloric acid and the product was extracted with ethyl acetate, washed with water and brine followed by complete evaporation of solvent to get the title compound which is taken to the next step without further purification.
  • the mixture is concentrated to approximately 20% of total volume. Methanol is added and recovered to remove borane derivatives. The product is extracted with ethyl acetate, washed with water and then brine. The organic layer is concentrated to approximately 20% of original volume. Tetrahydrofuran is then added and recovered completely under reduced pressure to get the title compound as a concentrated mass, which is taken to the next step.
  • the pH of the reaction mixture obtained above was adjusted to about 12 by adding 10% w/v aqueous sodium hydroxide solution at 25-30° C. and the resulting mixture was stirred for about 6 hours at 25-30° C.
  • the progress of the reaction was monitored by HPLC.
  • the pH of the reaction mixture was monitored and maintained at about 12 throughout the course of the reaction by adding 10% w/v aqueous sodium hydroxide solution. After the reaction was complete, the mass was filtered and concentrated to get the title compound as a white precipitate.
  • De-ionized water 500 mL
  • methanol 200 mL
  • methyl tertiary butyl ether 200 mL
  • the layers were separated.
  • the aqueous layer was washed with methyl tertiary butyl ether (200 mL), and filtered through hyflo bed.
  • the hyflo bed was washed with a mixture of methanol (25 mL) and methyl tertiary butyl ether (25 mL).
  • the filtrate was warmed to 50° C. and its pH adjusted to about 10 with concentrated hydrochloric acid.
  • the wet product was slurry washed with a mixture of methanol and de-ionized water (2:1, 100 mL) and filtered. The material was dried at 45° C. for 8 hours to yield 43.38 g of atorvastatin calcium.
  • the XRD spectrum of the product mainly showed two very broad peaks.
  • Atorvastatin calcium (2 g) obtained above was suspended in de-ionized water (20 ml) and stirred for 20 hours at about 30° C. The suspension was then filtered and dried under reduced pressure at 40 to 45° C. for 3 hours to get 1.9 g of the product.
  • the XRD spectrum of the product showed a change in pattern from that of the starting atorvastatin calcium. An increase in sharp peaks indicating increased crystallinity was observed.
  • Atorvastatin calcium (1.8 g, same as that used as starting compound in step I) and atorvastatin calcium (0.2 g, obtained from step I above) were suspended in a mixture of de-ionized water (34 ml) and methanol (6 ml). The temperature was raised slowly to 38 to 40° C. and the suspension was stirred for 16 hours at the same temperature. The suspension was then cooled to 35° C., filtered and dried under reduced pressure at 40 to 45° C. for 4 hours to get 1.9 g of the product. The XRD spectrum of the product showed a change in pattern from that of the starting atorvastatin calcium. The XRD spectrum of the product matched with that of Form-I of atorvastatin calcium.

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100056605A1 (en) * 2004-07-16 2010-03-04 Lek Pharmaceuticals D.D. Oxidative degradation products of atorvastatin calcium

Families Citing this family (33)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1577297A1 (en) * 2004-03-17 2005-09-21 Ranbaxy Laboratories, Ltd. Process for the production of atorvastatin calcium in amorphous form
JP2008510798A (ja) * 2004-08-27 2008-04-10 バイオコン・リミテッド 非晶質アトルバスタチンカルシウムのための方法
GB2424880A (en) * 2005-04-06 2006-10-11 Generics Crystalline forms of atorvastatin sodium, processes for their preparation and their use in inhibiting HMG-CoA reductase
WO2007020413A1 (en) 2005-08-15 2007-02-22 Arrow International Limited Crystalline and amorphous sodium atorvastatin
WO2007020421A1 (en) 2005-08-15 2007-02-22 Arrow International Limited Crystalline and amorphous sodium atorvastatin
GB0613567D0 (en) * 2006-07-07 2006-08-16 Arrow Int Ltd Crystalline sodium atorvastatin
GB0613566D0 (en) * 2006-07-07 2006-08-16 Arrow Int Ltd Crystalline sodium atorvastatin
ES2270722B1 (es) * 2005-09-15 2008-03-01 Ercros Industrial, S.A. Procedimiento para la obtencion de atorvastatina calcica amorfa.
GB0523637D0 (en) * 2005-11-21 2005-12-28 Avecia Pharmaceuticals Ltd Process and compounds
WO2007099552A2 (en) * 2006-03-02 2007-09-07 Matrix Labaratories Ltd Novel crystalline form of atovastatin hemi-magnesium
SI22255A (sl) * 2006-04-14 2007-10-31 Krka, Tovarna Zdravil, D.D., Novo Mesto Novi polimorfi statinovih soli in njihova uporabav farmacevtskih formulacijah
CN101205209B (zh) * 2007-12-25 2010-06-02 浙江新东港药业股份有限公司 一种阿伐他汀中间体的精制方法
EP2075246A1 (en) * 2007-12-27 2009-07-01 M. J. Institute of Research A process for preparation of amorphous form of atorvastatin hemi-calcium salt
CN101468963B (zh) * 2007-12-28 2012-09-19 石药集团中奇制药技术（石家庄）有限公司 一种无定形阿伐他汀钙的制备方法
KR100850558B1 (ko) * 2008-01-02 2008-08-06 조동옥 아토르바스타틴의 효율적인 제조방법
CN101560177B (zh) * 2008-04-16 2012-10-03 北京万全阳光医学技术有限公司 一种阿托伐他汀钙的制备方法
CN101429195B (zh) * 2008-11-03 2010-12-15 华东师范大学 一种高纯度阿托伐他汀重要合成中间体的制备方法
US8115015B2 (en) 2009-01-26 2012-02-14 Cadila Healthcare Limited Process for the preparation of amorphous atorvastatin calcium
WO2011131605A1 (en) * 2010-04-19 2011-10-27 Dsm Ip Assets B.V. Production of atorvastatin low in ether impurities
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Citations (35)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5003080A (en) 1988-02-22 1991-03-26 Warner-Lambert Company Process for trans-6-(2-(substituted-pyrrol-1-yl)alkyl)pryan-2-one inhibitors of cholesterol synthesis
US5097045A (en) 1989-02-01 1992-03-17 Warner-Lambert Company Process for trans-6-[2-(substituted-pyrrol-1-yl)alkyl]pyran-2-one inhibitors of cholesterol synthesis
US5103024A (en) 1990-10-17 1992-04-07 Warner-Lambert Company Process for the synthesis of (4r-cis)-1,1-dimethylethyl 6-cyanomethyl-2,2-dimethyl-1,3-dioxane-4-acetate
US5124482A (en) 1988-02-22 1992-06-23 Warner-Lambert Company Process for trans-6-(2-substituted-pyrrol-1-yl)alkyl)pyran-2-one inhibitors of cholesterol synthesis
US5149837A (en) 1988-02-22 1992-09-22 Warner-Lambert Company Process for trans-6-[2-(substituted-pyrrol-1-yl)alkyl]pyran-2-one inhibitors of cholesterol synthesis
US5155251A (en) 1991-10-11 1992-10-13 Warner-Lambert Company Process for the synthesis of (5R)-1,1-dimethylethyl-6-cyano-5-hydroxy-3-oxo-hexanoate
US5216174A (en) 1988-02-22 1993-06-01 Warner-Lambert Co. Process for trans-6-[12-(substituted-pyrrol-1-yl)alkyl]pyran-2-one inhibitors of cholesterol synthesis
US5245047A (en) 1988-02-22 1993-09-14 Warner-Lambert Company Process for trans-6-[2-(substituted-pyrrol-1-yl)alkyl]pyran-2-one inhibitors of cholesterol synthesis
US5248793A (en) 1990-10-17 1993-09-28 Warner-Lambert Company Process for the synthesis of (4R-cis)-1,1-dimethylethyl 6-iodomethyl or 6-(phenyl-substituted)sulfonyloxymethyl-2,2-dimethyl-1,3-dioxane-4-acetate
US5273995A (en) 1989-07-21 1993-12-28 Warner-Lambert Company [R-(R*R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl-3-phenyl-4-[(phenylamino) carbonyl]- 1H-pyrrole-1-heptanoic acid, its lactone form and salts thereof
US5342952A (en) 1993-03-03 1994-08-30 Warner-Lambert Company Process for trans-6-[2-(substituted-pyrrol-1-yl)alkyl]pyran-2-one inhibitors of cholesterol synthesis
WO1997003960A1 (en) 1995-07-17 1997-02-06 Warner-Lambert Company NOVEL PROCESS FOR THE PRODUCTION OF AMORPHOUS [R-(R*,R*)]-2-(4-FLUOROPHENYL)-β,δ-DIHYDROXY-5-(1-METHYLETHYL)-3-PHENYL-4-[(PHENYLAMINO)CARBONYL]-1H-PYRROLE-1-HEPTANOIC ACID CALCIUM SALT (2:1)
US5686104A (en) 1993-01-19 1997-11-11 Warner-Lambert Company Stable oral CI-981 formulation and process of preparing same
WO2000071116A1 (en) 1999-05-25 2000-11-30 Ranbaxy Laboratories Limited Process for the production of amorphous atorvastatin calcium
WO2001028999A1 (en) 1999-10-18 2001-04-26 EGIS Gyógyszergyár Rt. Process for the preparation of amorphous atorvastatin calcium
WO2001042209A1 (en) 1999-12-10 2001-06-14 Lek Pharmaceutical And Chemical Company D.D. Process for the preparation of amorphous atorvastatin
EP1148049A1 (en) 1995-07-17 2001-10-24 Warner-Lambert Company Crystalline R-(R*,R*)$-2-(4-fluorophenyl)-beta,delta-dihydroxy-5-(1-methylethyl)-3-phenyl-4- (phenylamino)carbonyl -1H-pyrrole-1-heptanoic acid hemi calcium salt (atorvastatin)
WO2001093860A1 (en) 2000-06-09 2001-12-13 Lek Pharmaceuticals D.D. Stabilized pharmaceutically effective composition and pharmaceutical formulation comprising the same
WO2002041834A2 (en) 2000-11-03 2002-05-30 Teva Pharmaceutical Industries, Ltd. Atorvastatin hemi-calcium form vii
WO2002051804A1 (en) 2000-12-27 2002-07-04 Ciba Specialty Chemicals Holding Inc. Crystalline forms of atorvastatin
WO2002057228A1 (en) 2001-01-17 2002-07-25 Biocon India Limited Atorvastatin calcium
WO2002057225A2 (en) 2000-12-18 2002-07-25 Merck & Co., Inc. Thrombin inhibitors
WO2002083638A1 (en) 2001-04-11 2002-10-24 Cadila Healthcare Limited Process for the production of atorvastatin calcium in amorphous form
US20020183378A1 (en) 2000-11-30 2002-12-05 Judith Aronhime Novel crystal forms of atorvastatin hemi-calcium and processes for their preparation as well as novel processes for preparing other forms
WO2003004470A1 (en) 2001-06-29 2003-01-16 Warner-Lambert Company Llc Crystalline forms of 'r-(r*,r*)!-2-(4-fluorophenyl)-beta, delta-dihydroxy-5-(1-methylethyl)-3-phenyl-4-'phenylamino)carbonyl!-1h-pyrrole-1-heptanoic acid calcium salt (2:1) (atorvastatin)
WO2003011826A1 (en) 2001-07-30 2003-02-13 Dr. Reddy's Laboratories Ltd. Crystalline forms vi and vii of atorvastatin calcium
WO2003018547A2 (en) 2001-08-31 2003-03-06 Morepen Laboratories Ltd. An improved process for the preparation of amorphous atorvastatin calcium salt (2:1)
US20030109569A1 (en) 2001-01-23 2003-06-12 Gorazd Sorsak Preparation of pharmaceutically acceptable atorvastatin salts in non-crystalline form
WO2003068739A1 (en) 2002-02-01 2003-08-21 Zentiva A.S. Method of manufacturing an amorphous form of the hemi-calcium salt of (3r, 5r) 7- 3-phenyl-4-phenylcarbamoyl-2-(4-fluorophenyl)-5-isopropyl-pyrrol-1-yl!-3, 5-dihydroxyheptanoic acid (atorvastatin)
WO2003078379A1 (en) 2002-03-18 2003-09-25 Biocon Limited AMORPHOUS Hmg-CoA REDUCTASE INHIBITORS OF DESIRED PARTICLE SIZE
US6646133B1 (en) 2000-10-17 2003-11-11 Egis Gyogyszergyar Rt. Process for the preparation of amorphous atorvastatin calcium
WO2003099785A1 (en) 2002-05-28 2003-12-04 Cadila Healthcare Limited Process for the preparation of amorphous atorvastatin calcium
US20040077708A1 (en) 2002-10-11 2004-04-22 Rok Grahek Stablized pharmaceutical composition comprising an amorphous active substance
WO2004085391A1 (en) 2003-03-24 2004-10-07 Richter Gedeon Vegyészeti Gyár Rt. Process for the synthesis of amorphous atorvastatin calcium
WO2006037125A1 (en) 2004-09-28 2006-04-06 Teva Pharmaceutical Industries Ltd. Process for preparing forms of atorvastatin calcium substantially free of impurities

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1577297A1 (en) * 2004-03-17 2005-09-21 Ranbaxy Laboratories, Ltd. Process for the production of atorvastatin calcium in amorphous form

Patent Citations (42)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5003080A (en) 1988-02-22 1991-03-26 Warner-Lambert Company Process for trans-6-(2-(substituted-pyrrol-1-yl)alkyl)pryan-2-one inhibitors of cholesterol synthesis
US5124482A (en) 1988-02-22 1992-06-23 Warner-Lambert Company Process for trans-6-(2-substituted-pyrrol-1-yl)alkyl)pyran-2-one inhibitors of cholesterol synthesis
US5149837A (en) 1988-02-22 1992-09-22 Warner-Lambert Company Process for trans-6-[2-(substituted-pyrrol-1-yl)alkyl]pyran-2-one inhibitors of cholesterol synthesis
US5280126A (en) 1988-02-22 1994-01-18 Warner-Lambert Company Process for trans-6-[2-(substituted-pyrrol-1-yl)alkyl]pyran-2-one inhibitors of cholesterol synthesis
US5216174A (en) 1988-02-22 1993-06-01 Warner-Lambert Co. Process for trans-6-[12-(substituted-pyrrol-1-yl)alkyl]pyran-2-one inhibitors of cholesterol synthesis
US5245047A (en) 1988-02-22 1993-09-14 Warner-Lambert Company Process for trans-6-[2-(substituted-pyrrol-1-yl)alkyl]pyran-2-one inhibitors of cholesterol synthesis
US5097045A (en) 1989-02-01 1992-03-17 Warner-Lambert Company Process for trans-6-[2-(substituted-pyrrol-1-yl)alkyl]pyran-2-one inhibitors of cholesterol synthesis
US5273995A (en) 1989-07-21 1993-12-28 Warner-Lambert Company [R-(R*R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl-3-phenyl-4-[(phenylamino) carbonyl]- 1H-pyrrole-1-heptanoic acid, its lactone form and salts thereof
US5248793A (en) 1990-10-17 1993-09-28 Warner-Lambert Company Process for the synthesis of (4R-cis)-1,1-dimethylethyl 6-iodomethyl or 6-(phenyl-substituted)sulfonyloxymethyl-2,2-dimethyl-1,3-dioxane-4-acetate
US5103024A (en) 1990-10-17 1992-04-07 Warner-Lambert Company Process for the synthesis of (4r-cis)-1,1-dimethylethyl 6-cyanomethyl-2,2-dimethyl-1,3-dioxane-4-acetate
US5155251A (en) 1991-10-11 1992-10-13 Warner-Lambert Company Process for the synthesis of (5R)-1,1-dimethylethyl-6-cyano-5-hydroxy-3-oxo-hexanoate
US5686104A (en) 1993-01-19 1997-11-11 Warner-Lambert Company Stable oral CI-981 formulation and process of preparing same
US5342952A (en) 1993-03-03 1994-08-30 Warner-Lambert Company Process for trans-6-[2-(substituted-pyrrol-1-yl)alkyl]pyran-2-one inhibitors of cholesterol synthesis
US5397792A (en) 1993-03-03 1995-03-14 Warner-Lambert Company Process for trans-6-[2-(substituted-pyrrol-1-yl)alkyl]pyran-2-one inhibitors of cholesterol synthesis
EP1148049A1 (en) 1995-07-17 2001-10-24 Warner-Lambert Company Crystalline R-(R*,R*)$-2-(4-fluorophenyl)-beta,delta-dihydroxy-5-(1-methylethyl)-3-phenyl-4- (phenylamino)carbonyl -1H-pyrrole-1-heptanoic acid hemi calcium salt (atorvastatin)
WO1997003960A1 (en) 1995-07-17 1997-02-06 Warner-Lambert Company NOVEL PROCESS FOR THE PRODUCTION OF AMORPHOUS [R-(R*,R*)]-2-(4-FLUOROPHENYL)-β,δ-DIHYDROXY-5-(1-METHYLETHYL)-3-PHENYL-4-[(PHENYLAMINO)CARBONYL]-1H-PYRROLE-1-HEPTANOIC ACID CALCIUM SALT (2:1)
US6528660B1 (en) 1999-05-25 2003-03-04 Ranbaxy Laboratories Limited Process for the production of amorphous atorvastatin calcium
WO2000071116A1 (en) 1999-05-25 2000-11-30 Ranbaxy Laboratories Limited Process for the production of amorphous atorvastatin calcium
WO2001028999A1 (en) 1999-10-18 2001-04-26 EGIS Gyógyszergyár Rt. Process for the preparation of amorphous atorvastatin calcium
CA2392025A1 (en) 1999-12-10 2001-06-14 Lek Pharmaceutical And Chemical Company D.D. Process for the preparation of amorphous atorvastatin
WO2001042209A1 (en) 1999-12-10 2001-06-14 Lek Pharmaceutical And Chemical Company D.D. Process for the preparation of amorphous atorvastatin
US6613916B2 (en) 1999-12-10 2003-09-02 Lek Pharmaceuticals D.D. Process for the preparation of amorphous atorvastatin
WO2001093860A1 (en) 2000-06-09 2001-12-13 Lek Pharmaceuticals D.D. Stabilized pharmaceutically effective composition and pharmaceutical formulation comprising the same
US6646133B1 (en) 2000-10-17 2003-11-11 Egis Gyogyszergyar Rt. Process for the preparation of amorphous atorvastatin calcium
WO2002041834A2 (en) 2000-11-03 2002-05-30 Teva Pharmaceutical Industries, Ltd. Atorvastatin hemi-calcium form vii
US20020183378A1 (en) 2000-11-30 2002-12-05 Judith Aronhime Novel crystal forms of atorvastatin hemi-calcium and processes for their preparation as well as novel processes for preparing other forms
WO2002057225A2 (en) 2000-12-18 2002-07-25 Merck & Co., Inc. Thrombin inhibitors
WO2002051804A1 (en) 2000-12-27 2002-07-04 Ciba Specialty Chemicals Holding Inc. Crystalline forms of atorvastatin
WO2002057228A1 (en) 2001-01-17 2002-07-25 Biocon India Limited Atorvastatin calcium
US20030109569A1 (en) 2001-01-23 2003-06-12 Gorazd Sorsak Preparation of pharmaceutically acceptable atorvastatin salts in non-crystalline form
WO2002083637A1 (en) 2001-04-11 2002-10-24 Cadila Healthcare Limited Process for the production of amorphous atorvastatin calcium
WO2002083638A1 (en) 2001-04-11 2002-10-24 Cadila Healthcare Limited Process for the production of atorvastatin calcium in amorphous form
WO2003004470A1 (en) 2001-06-29 2003-01-16 Warner-Lambert Company Llc Crystalline forms of 'r-(r*,r*)!-2-(4-fluorophenyl)-beta, delta-dihydroxy-5-(1-methylethyl)-3-phenyl-4-'phenylamino)carbonyl!-1h-pyrrole-1-heptanoic acid calcium salt (2:1) (atorvastatin)
WO2003011826A1 (en) 2001-07-30 2003-02-13 Dr. Reddy's Laboratories Ltd. Crystalline forms vi and vii of atorvastatin calcium
CA2456095A1 (en) 2001-08-31 2003-03-06 Morepen Laboratories Ltd. An improved process for the preparation of amorphous atorvastatin calcium salt (2:1)
WO2003018547A2 (en) 2001-08-31 2003-03-06 Morepen Laboratories Ltd. An improved process for the preparation of amorphous atorvastatin calcium salt (2:1)
WO2003068739A1 (en) 2002-02-01 2003-08-21 Zentiva A.S. Method of manufacturing an amorphous form of the hemi-calcium salt of (3r, 5r) 7- 3-phenyl-4-phenylcarbamoyl-2-(4-fluorophenyl)-5-isopropyl-pyrrol-1-yl!-3, 5-dihydroxyheptanoic acid (atorvastatin)
WO2003078379A1 (en) 2002-03-18 2003-09-25 Biocon Limited AMORPHOUS Hmg-CoA REDUCTASE INHIBITORS OF DESIRED PARTICLE SIZE
WO2003099785A1 (en) 2002-05-28 2003-12-04 Cadila Healthcare Limited Process for the preparation of amorphous atorvastatin calcium
US20040077708A1 (en) 2002-10-11 2004-04-22 Rok Grahek Stablized pharmaceutical composition comprising an amorphous active substance
WO2004085391A1 (en) 2003-03-24 2004-10-07 Richter Gedeon Vegyészeti Gyár Rt. Process for the synthesis of amorphous atorvastatin calcium
WO2006037125A1 (en) 2004-09-28 2006-04-06 Teva Pharmaceutical Industries Ltd. Process for preparing forms of atorvastatin calcium substantially free of impurities

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
Brower et al, "The Synthesis of (4R-cis)-1,1-Dimethylethyl 6-cyanomethy1-2,2-dimethyl-1,3-dioxane-4-acetate, a Key Intermediate for the Preparation of CI-981, a Highly Potent, Tissue Selective Inhibitor of HMG-CoA Reductase", Tetrahedron Letters, 33(17):2279-2282 (1992).
Pavia et al. Introduction to Organic Laboratory Techniques 1990, pp. 577-596. *
Shimako et al, "Atorvastatin (CI-981) Clinical Pharmacokinetic Study (I): Relative Bioavailability of Amorphous and Crystalline Preparations of Atorvastatin", Japanese Pharmacology and Therapeutics, 26(8):1241-1252 (1998).
Wade et al., "In Pursuit of Higher Purity: Use of 13C NMR and 13C-Enriched Substrates to Trace Impurity Generation and Removal in the Synthesis of Atorvastatin", Organic Process Research and Development, 1(4):320-324 (1997).

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100056605A1 (en) * 2004-07-16 2010-03-04 Lek Pharmaceuticals D.D. Oxidative degradation products of atorvastatin calcium

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